This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. M2 protein in influenza A virus has an ion channel activity in transmembrane domain (TM) and is required for the acidification of the virion and efficient viral ribonucleoprotein uncoating during viral entry into the host. Adamantane based antiviral drugs, amantadine and rimantadine were previously shown effective in treating influenza by inhibiting M2 channel activity. We have recently determined the structures of TM (wildtype) in apo and amantadine bound forms at medium and low resolutions respectively. Elucidation of inhibitory mechanism by drug needs the understanding of interactions between drug and protein at atomic level, thus there is a requirement of high resolution structures of protein-drug complexes. In the view of designing novel M2 inhibitors, we are working towards crystallizing drug resistance mutants.